Combined segregation-linkage analysis of plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels with TAR gene polymorphisms

By decreasing plasminogen binding to fibrin surface, the thrombin activatab le fibrinolysis inhibitor (TAFI) has been hypothesized to constitute an ear ly marker for atherothrombotic diseases. Previous studies have shown that p lasma TAFI levels exhibit a high interindividual variability that is only p oorly explained by lifestyle factors. Several polymorphisms of the TAFI gen e have been described, and a combination of a C+1542G substitution in the 3 ' untranslated region and an Ala147Thr amino acid change has been shown to explain 60% of TAFI variability in a sample of unrelated individuals. A seg regation-linkage analysis was performed to determine whether these polymorp hisms are directly involved in the genetic regulation of TAFI levels, or wh ether they are only markers in linkage disequilibrium (LD) with unmeasured TAFI-linked quantitative trait loci (QTLs). The sample consisted of 97 heal thy nuclear families from the Stanislas Cohort. The C+1542G and Ala147Thr p olymorphisms were in complete negative LD, with minor allele frequencies of 0.27 and 0.28, respectively. Results of the segregation-linkage analysis p rovided evidence of two TAFI-linked QTLs in LD with the two measured polymo rphisms, which would explain 78% of the TAFI variance, as compared with 55% explained by the C+1542G and the Ala147Thr polymorphisms combined. The two putative QTLs would have minor allele frequencies of 0.45 and 0.32, respec tively. The hypothesis that one of the measured polymorphisms is one of the QTLs was rejected. The putative QTLs also did not seem compatible with the other TAFI gene polymorphisms that we have previously described. More exte nsive sequencing of the TAFI gene is necessary to identify the functional v ariants.